3-trifuoromethylsulfonyloxy-substituted 1-carbacephalosporins as intermediates for antibiotics

ABSTRACT

7β-Acylamino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylic acid antibiotic compounds, esters and salts thereof, and the corresponding 7-amino and protected 7-amino 1-carbacephalosporins are provided. The 3-trifluoromethylsulfonyloxy-substituted 1-carbacephalosporins also are useful in a process for preparing 3-halo-1-carbacephalosporins which comprises reacting a 3-triflate ester with a lithium halide in an aprotic polar solvent.

The United States government has rights in this invention by virtue ofGrant No. GM-33328 awarded by the National Institutes of Health.

This application is a division of application Ser. No. 018,668, filed2-25-87 now U.S. Pat. No. 478,884, which is a division of applicationSer. No. 08/761,647, filed 8/2/85, now U.S. Pat. No. 4,673,737.

BACKGROUND OF THE INVENTION

This invention relates to 1-carba(1-dethia)-3-cephem-4-carboxylic acidsand derivatives thereof. In particular, it relates to 7-acylamino-(or7-amino)-3-trifluoromethylsulfonyloxy-1-carba(1-dethia)-3-cephem-4-carboxylicacids and esters thereof and to a process for preparing 3-chloro and3-bromo-1-carba (1-dethia)-3-cephem-4-carboxylic acids with the3-trifluoromethylsulfonyloxy derivatives.

The 1-carba(1-dethia)-3-cephem-4-carboxylic acids, hereinafter1-carbacephalosporins, possess the 4,6-bicyclo ring system representedby the following formula ##STR1## wherein the numbering of the cephamnomenclature system is used for convenience.

The preparation of 1-carbacephalosporins and C-3 substituted methylderivatives thereof is taught broadly by Christensen et al., U.S. Pat.No. 4,226,866. Hirata et al., U.K. Patent Application No. 2041923 teacha process for preparing 3-H and 3-halo 1-carbacephalosporins, whileHatanaka et al., Tetrahedron Letters, 24, [No. 44], pp. 4837-4838(1983), teach a process for preparing a3-hydroxy-(±)-1-carbacephalosporin. Because of the importance of thesenewer β-lactam antibiotics, there is a need for better methods for theirpreparation and for 1-carbacephalosporins with enhanced potency againstinfectious and resistant microorganisms.

DETAILED DESCRIPTION

The 1-carbacephalosporin compounds provided by this invention arerepresented by the formula 1 ##STR2## wherein A is hydrogen, anamino-protecting group, or an acyl group ##STR3## wherein R is hydrogen;C₁ -C₆ alkyl, C₁ -C₆ alkyl substituted by cyano, carboxy, halogen,amino, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio, or trifluoromethylthio; a phenylor substituted phenyl group represented by the formula wherein a and a'independently are hydrogen, halogen, hydroxy, C₁ -C₄ alkoxy, C₁ -C₄alkanoyloxy, C₁ -C₄ alkyl, C₁ -C₄ alkylthio, amino, C₁ -C₄alkanoylamino, C₁ -C₄ alkylsulfonylamino, carboxy, carbamoyl,hydroxymethyl, aminomethyl, or carboxymethyl;

a group represented by the formula ##STR4## wherein a and a' have thesame meanings as defined above, Z is O or S, and m is 0 or 1; aheteroarylmethyl group represented by the formula

    R.sup.1 --CH.sub.2 --

wherein R¹ is thienyl, furyl, benzothienyl, benzofuryl, indolyl,triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,and such heteroaryl groups substituted by amino, hydroxy, halogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkylsulfonylamino;

a substituted methyl group represented by the formula ##STR5## whereinR² is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl grouprepresented by the formula ##STR6## wherein a and a' have the abovedefined meanings, or R² is R¹ as defined above, and Q is hydroxy, C₁ -C₄alkanoyloxy, carboxy, sulfo, amino, or a substituted amino grouprepresented by the formula ##STR7## wherein R' is hydrogen or C₁ -C₃alkyl, R" is C₁ -C₄ alkyl, furyl, thienyl, phenyl, halophenyl,nitrophenyl, styryl, halostyryl, nitrostyryl or a group ##STR8## whereinR' is hydrogen or C₁ -C₃ alkyl, and R"' is hydrogen, C₁ -C₃alkylsulfonyl, C₁ -C₃ alkyl, or C₁ -C₄ alkanoyl; or Q is a substitutedamino group represented by the formula ##STR9## wherein R"' has the samemeanings as defined above and q is 2 or 3; or Q is a substituted aminogroup represented by the formula ##STR10## or a benzamido grouprepresented by the formula ##STR11## wherein t is 1 to 3; or R is a ketogroup or an oximino-substituted group represented by the formulae##STR12##

wherein R₃ is R¹ or R₂ as defined above and R₄ is hydrogen, C₁ -C₄alkyl, or a carboxysubstituted alkyl or cycloalkyl group represented bythe formula ##STR13## wherein b and b' independently are hydrogen, C₁-C₃ alkyl, and b and b' when taken together with the carbon to whichthey are bonded form ya 3- to 6-membered carbocyclic ring, and R⁵ ishydroxy, C₁ -C₄ alkoxy, amino, C₁ -C₄ alkylamino, or di(C₁ -C₄alkyl)amino,

R₁ is hyrogen or a carboxy-protecting group; and when R₁ is hydrogen,the pharmaceutically acceptable non-toxic salts thereof.

The compounds represented by the formula 1, wherein A is an acyl groupRCO and R₁ is hydrogen and the pharmaceutically acceptable non-toxicsalts thereof, inhibit the growth of microorganisms pathogenic to manand animals. The compounds in esterified form (R₁ =carboxy-protectinggroup) are useful in a process for preparing 3-chloro and3-bromo-1-carba-3-cephem esters and acids as described hereinafter. Such3-halo-1-carba-3-cephem-4-carboxylic acids and salts thereof are alsoantibiotics useful in the treatment of infectious diseases in man andanimals.

In the above definition of the compounds represented by the formula 1,C₁ -C₆ alkyl refers to the straight and branched chain alkyl groups suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl,n-hexyl, 3-methylpentyl, and like alkyl groups; C₁ -C₆ alkyl substitutedby cyano refers to cyanomethyl, cyanoethyl, 4-cyanobutyl, and the like;C₁ -C₆ alkyl substituted by carboxy refers to such groups ascarboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 4-carboxybutyl,5-carboxypentyl, and the like; C₁ -C₆ alkyl substituted by halogenrefers to chloromethyl, bromomethyl, 2-chloroethyl, 1-bromoethyl,4-chlorobutyl, 4-bromopentyl, 6-chlorohexyl, 4-fluorobutyl,3-fluoropropyl, fluoromethyl, and the like; C₁ -C₆ alkyl substituted byamino refers to such groups as 2-aminoethyl, aminomethyl, 3-aminopropyland 4-aminobutyl; C₁ -C₆ alkyl substituted by C₁ -C₄ alkoxy refers tomethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, ethoxymethyl,3-propoxypropyl, 3-ethoxybutyl, 4-t-butyloxybutyl, 3-methoxypentyl,6-methoxyhexyl, and like group; C₁ -C₆ alkyl substituted by C₁ -C₄-alkylthio refers to such groups as for example methylthiomethyl,2-methylthioethyl, 2-ethylthiopropyl, 4 -methylthiobutyl,5-ethylthiohexyl, 3-t-butylthiopropyl, and like groups; C₁ -C₆ alkylsubstituted by trifluoromethyl is exemplified by 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and the like; and C₁ -C₆alkyl substituted by trifluoromethylthio refers to, for example,trifluoromethylthiomethyl, 2-trifluoromethylthioethyl,2-trifluoromethylthiopropyl, 4-trifluoromethylthiobutyl,5-trifluoromethylthiohexyl, and like C₁ -C₆ alkyl substituted groups.

When in the formula 1 R is a substituted phenyl group wherein thesubstituent(s) are represented by a and a', examples of such groups arehalophenyl such as 4-chlorophenyl, 3-bromophenyl, 2-fluorophenyl,2,4-dichlorophenyl, and 3,5-dichlorophenyl; hydroxyphenyl such as2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl,and 3,4-dihydroxyphenyl; alkoxyphenyl, such as 2,6-dimethoxyphenyl,4-methoxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl,4-t-butyloxyphenyl, 4-methoxy-3-ethoxyphenyl, and 4-n-propoxyphenyl;alkanoyloxyphenyl such as 2-acetoxyphenyl, 4-propionoxyphenyl,4-formyloxyphenyl, 4-acetoxyphenyl, 3-butyryloxyphenyl, and3-acetoxyphenyl; alkylphenyl such as 4-methylphenyl, 2-methylphenyl,2,4-dimethylphenyl, 3-t-butylpheny, 4-ethylphenyl,4-ethyl-3methylphenyl, and 3,5-dimethylphenyl; alkylthiophenyl such as4-methylthiophenyl, 3-n-butylthiophenyl, 2-ethylthiophenyl,3,4-dimethylthiophenyl, and 3-n-propylthiophenyl; aminophenyl such as2-aminophenyl, 4-aminophenyl, 3,5-diaminophenyl, and 3-aminophenyl;alkanoylamino such as 2-acetylamino, 4-acetylamino, 3-propionylamino,and 4-butyrylamino; alkylsulfonylamino such a 3 -methylsulfonylamino,4-methylsulfonylamino, 3,5-(dimethylsulfonylamino)phenyl,4-n-butylsulfonylaminophenyl, and 3-ethylsulfonylaminophenyl;carboxyphenyl such as 2-, 3-, or 4-, carboxyphenyl, 3,4-dicarboxyphenyl,and 2,4-dicarboxyphenyl; carbamoylphenyl such as 2-carbamoylphenyl,2,4-dicarbamoylphenyl, and 4-carbamoylphenyl; hydroxymethylphenyl suchas 4-hydroxymethylphenyl and 2-hydroxymethylphenyl; aminomethylphenylsuch as 2-aminomethylphenyl and 3-aminomethylphenyl; and carboxyphenylsuch as 2-carboxymethylphenyl, 4-carboxymethylphenyl, and3,4-dicarboxymethylphenyl; and the substituted phenyl groups bearingdifferent substituents such as 4-chloro-3-methylphenyl,4-fluoro-3-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl,4-hydroxy-3-chlorophenyl, 4-hydroxy-3-methylphenyl,4-ethyl-3-hydroxyphenyl, 4-methoxy-3-hydroxyphenyl,4-t-butyloxy-2-hydroxyphenyl, 4-acetylamino-3-methoxyphenyl,3-amino-4-ethylphenyl, 2-aminomethyl-4-chlorophenyl,2-hydroxymethyl-3-methoxyphenyl, 2-hydroxymethyl-4-fluorophenyl,2-acetoxy-4-aminophenyl, 4-acetoxy-3-methoxyphenyl,3-isopropylthio-4-chlorophenyl, 2-methylthio-4-hydroxymethylphenyl,4-carboxy-3-hydroxyphenyl, 4-ethoxy-3-hydroxyphenyl,4-methylsulfonylamino-2-carboxyphenyl, 4-amino-3-chlorophenyl, and2-carboxymethyl-4-hydroxyphenyl.

Examples of RCO- groups of the formula 1 wherein R is a grouprepresented by the formula ##STR14## with m=0 are: phenylacetyl,4-hydroxyphenylacetyl, 4-chlorophenylacetyl, 3,4-dichlorophenylacetyl,4-methoxyphenylacetyl, 3-ethoxyphenylacetyl, 2-aminomethylphenylacetyl,3-carboxyphenylacetyl, 4-acetoxyphenylacetyl, 3-aminophenylacetyl, and4-acetylaminophenylacetyl; and with m=1 and Z=0, phenoxyacetyl,4-chlorophenoxyacetyl, 4-fluorophenoxyacetyl, 3-aminophenoxyacetyl,3-hydroxyphenoxyacetyl, 2-methoxyphenoxyacetyl,2-methylthiophenoxyacetyl, 4-acetylaminophenoxyacetyl,3,4-dimethylphenoxyacetyl, and 3-hydroxymethylphenoxyacetyl; and withm=1 and Z=S, phenylthioacetyl, 4-chlorophenylthioacetyl,3,4-dichlorophenylthioacetyl, 2-fluorophenylthioacetyl,3-hydroxyphenylthioacetyl, and 4-ethoxyphenylthioacetyl.

Examples of R¹ --CH₂ CO-groups of the formula 1 wherein R¹ is aheteroaryl group are: 2-thienylacetyl, 3-thienylacetyl, 2-furylacetyl,2-benzothienylacetyl, 2-benzofurylacetyl, indol-2-ylacetyl,1H-tetrazol-1-ylacetyl, oxazol-2-ylacetyl, oxazol-4-ylacetyl,thiazol-4-ylacetyl, 2-aminothiazol-4-ylacetyl,1,3,4-oxadiazol-2-ylacetyl, 1,3,4-thiadiazol-2-ylacetyl,5-ethyl-1,3,4-oxadiazol-2-ylacetyl, and like heteroaryl groupsoptionally substituted by amino, C₁ -C₄ alkylsulfonylamino, hydroxy,halo, C₁ -C₄ alkyl or C₁ -C₄ -alkoxy groups.

Examples of RCO- groups of the formula 1 compounds wherein R is asubstituted methyl group represented by the formula R² --CH(Q)- and Q isamino, carboxy, hydroxy, or sulfo, are 2-carboxy-2-phenylacetyl,2-carboxy-2-(4-hydroxyphenyl)acetyl, 2-amino-2-phenylacetyl,2-amino-2-(4-hydroxyphenyl)acetyl,2-amino-2-(3-chloro-4-hydroxyphenyl)acetyl,2-amino-2-(cyclohex-1,4-dien-1-yl)acetyl, 2-hydroxy-2-phenylacetyl,2-formyloxy-2-phenylacetyl, 2-sulfo-2-phenylacetyl,2-sulfo-2-(4-methylphenyl)acetyl, and2-acetoxy-2-(3-hydroxyphenyl)acetyl, 2-amino-2-(2-thienyl)acetyl,2-amino-2-(3-benzothienyl)acetyl, 2-amino-2-(1H-tetrazol-1-yl)acetyl,2-hydroxy-2-(1,3,4-thiadiazol-2yl)acetyl,2-amino-2-(2-aminothiazol-4-yl)acetyl, 2-carboxy-2-(2-thienyl)acetyl,2-carboxy-2-(benzothien-2-yl)acetyl, and2-hydroxy-2-(benzofur-2-yl)acetyl; and when Q is a substituted aminogroup represented by the formula ##STR15## examples of such acyl groupsare 2-(N-methyl-N-benzoylcarbamoylamino)-2-phenylacetyl,2-(N-methyl-N-cinnamoylcarbamoylamino)-2-(2-furyl)acetyl,2-(N,N-dimethylcarbamoylureido)-2-(4-chlorophenyl)acetyl,2-[N-methyl-N-(2-chlorocinnamoyl)carbamoylamino]-2-(2-thienyl)acetyl,and 2-(N-ethyl-N-acetylcarbamoylamino)-2-(4-hydroxyphenyl)acetyl; andwhen Q is a substituted amino group represented by the formula ##STR16##examples of acyl group R(CO--) are2-[(3-methylimidazolidin-2-one-1-yl)carbonylamino]-2-phenylacetyl,2-[(3-acetylimidazolindin-2-one-1-yl)carbonylamino]-2-phenylacetyl,2-[(3-methylsulfonylimidazolidin-2-one-1-yl)-2-(2-thienyl)acetyl, and2-[(3-acetylhexahydropyrimidin-2-one-1-yl)carbonylamino]-2-phenylacetyl;and when Q is a hydroxy-substituted benzamido group represented by theformula ##STR17## examples of such acyl groups are2-(2,4-dihydroxybenzamido)-2-phenylacetyl,2-(4-hydroxybenzamido)-2-(4-hydroxyphenyl)acetyl,2-(3,4-dihydroxybenzamido)-2-(2-aminothiazol-4-yl)acetyl,2-(3,5-dihydroxybenzamido)-2-(3-thienyl)acetyl, and2-(2-hydroxybenzamido)-2-(2-benzofuryl)acetyl.

Examples of RCO acyl groups of the compounds represented by formula 1when R is a keto group or an oximino-substituted group represented bythe formulae ##STR18## are the keto groups 2-oxo-2-phenylacetyl,2-oxo-2-(2-thienyl)acetyl, 2-oxo-2-(2-aminothiazol-4-yl)acetyl; andoximino-substituted groups 2-phenyl-2-methoxyiminoacetyl,2-(2-thienyl)-2-ethoxyiminoacetyl, 2-(2-furyl)-2-methoxyiminoacetyl,2-(2-benzothienyl)-2-carboxymethoxyiminoacetyl,2-(2-thienyl)-2-(2-carboxyethoxy)iminoacetyl,2-(2-amino-1,2,4-thiadiazol-4-yl)-2-methoxyiminoacetyl,2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl,2-(2-chlorothiazol-4-yl)-2-methoxyiminoacetyl,2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-yl)oxyiminoacetyl,2-(2-aminothiazol-4-yl)-2-(2-carbamoylprop-2-yl)oxyiminoacetyl, and2-(5-amino-1,3,4-thiadiazol-2-yl)-2-methoxyiminoacetyl.

The carboxy-protecting group R¹ is a conventional carboxy-blocking groupused in the β-lactam antibiotic art and serves the function of blockingthe acidic carboxy group while reactions are carried out at other sitesin the molecule. Such groups are used for the temporary protection orblocking of the carboxy group. Examples of such groups are t-butyl,haloalkyl groups, e.g. 2,2,2-trichloroethyl, 2-iodoethyl, allyl,1,1-dimethylprop-2-yne-1-yl, benzyl, substituted benzyl, e.g.4-nitrobenzyl, and 4-methoxybenzyl, diphenylmethyl, trialkylsilyl ormixed alkylarylsilyl groups, e.g. trimethylsilyl, triethylsilyl,dimethylphenylsilyl, β-trimethylsilylethyl, and β-methylsulfonylethyl.

The 3-trifluoromethylsulfonyloxy-1-carbacephalosporins represented bythe formula 1 wherein A is RCO or an amino-protecting group are preparedby the O-acylation of the corresponding 3-hydroxy-1-carbacephalosporinester as illustrated below. ##STR19## wherein R₁ is a carboxy-protectinggroup. During the acylation any reactive groups in the side chain groupR also capable of acylation is desirably protected. For example, anyamino group substituents are protected with a conventionalamino-protecting group to prevent amide formation in competition withthe desired ester formation. The acylation is carried out in an inertsolvent at a temperature between about 0° C. and about 35° C. in thepresence of a tertiary amine. Amines which are suitable includetriethylamine, tri-n-butylamine, pyridine, diethyl-t-butylamine,diisopropylethylamine, and like amines. Hindered trialkylamines arepreferred. The acylating reagent can be trifluoromethanesulfonicanhydride (triflic anhydride) or trifluoromethanesulfonyl chloride(triflic chloride) or other suitable acid derivative oftrifluoromethanesulfonic acid. Inert solvents useful in the process arethe halogenated hydrocarbons such as chloroform, methylene chloride,trichloroethane and the like; ether solvents such as tetrahydrofuran,esters such as ethyl acetate; or other inert solvents, e.g.acetonitrile.

The triflic esters are recovered from the reaction mixture byconventional isolation methods, e.g. by extraction. Following theesterification the C4 carboxy-protecting group R₁ is removedtto providefree acid 3-triflic ester where in formula 1 R₁ is hydrogen.Alternatively, the carboxy-protecting group can be left intact and thediester used in the process described hereinafter for the preparation ofthe corresponding 3-chloro-1-carbacephalosporin.

The 3-trifluoromethanesulfonyloxy compounds represented by the formula 1are also prepared by the N-acylation of a7-amino-3-trifluoromethanesulfonyloxy-1-carba-3-cephem-4-carboxylic acidester (formula 1, A=hydrogen) with the carboxylic acid RCOOH wherein Rhas the same meanings as defined for formula 1. An active derivative ofthe carboxy group of the acid is desirably used in the acylation. Forexample, acid halides, acid azides and active esters or acid anhydridesmay be used in the acylation. Likewise, the free acid may be coupledwith the amine in the presence of a dehydrating agent such as acarbodiimide, e.g. dicyclohexycarbodiimide.

Active esters of the carboxylic acid such as those formed withN-hydroxysuccinimide and hydroxybenztriazole or those formed with thehaloformates, e.g. ethyl chloroformate and isobutyl chloroformate, maybe used.

The N-acylation of a 7-amino-3-trifluoromethylsulfonyloxy-3-cephem esteris illustrated below ##STR20## wherein R has the same meanings asdefined for formula 1, R₁ is a carboxy-protecting group, and Xrepresents OH (free acid), OCOR (anhydride), or a reactive derivative,for example chloro.

The N-acylations are carried out by using the methods employed for theacylation of the cephalosporin nuclei such as 7-ACA and 7-ADCA. In anexample of the acylation benzyl7-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate inacetonitrile is treated with phenoxyacetyl chloride in the presence ofan acid-binding agent such as triethylamine or pyridine to providebenzyl7-phenoxyacetylamino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate.

The compounds represented by the formula 1 wherein Q is a substitutedamino group are obtained by N-acylation of a compound wherein Q isamino. For the compound represented by the formula ##STR21## wherein R₁is a carboxy-protecting group, is acylated in the presence of an acidscavenger with a compound represented by the formulae ##STR22## whereinR', R", R"', t and q have the same meanings as defined for formula 1.

Examples of 3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylicacids and esters of the invention represented by the formula 1 are shownbelow.

    ______________________________________                                        R                      R.sub.1                                                ______________________________________                                        H                      benzyl                                                 CH.sub.3 --            "                                                      NCCH.sub.2 --          "                                                      Cl--CH.sub.2 --        pMB                                                    CF.sub.3 SCH.sub.2 --  H                                                      2,6-dimethoxyphenyl    H                                                      4-methylphenyl         H                                                      4-chlorophenyl         benzyl                                                 3-hydroxyphenyl        "                                                      phenoxymethyl          "                                                        "                    H                                                        "                    pNB                                                    4-chlorophenoxymethyl  H                                                      4-hydroxyphenoxymethyl H                                                      phenylthiomethyl       H                                                      benzyl                 H                                                        "                    benzyl                                                 4-chlorophenylthiomethyl                                                                             H                                                      4-fluorophenylthiomethyl                                                                             H                                                      4-chlorobenzyl         H                                                      2-aminomethylbenzyl    H                                                      3-carboxymethylbenzyl  H                                                      2-thienylmethyl        benzyl                                                   "                    H                                                        "                    pNB                                                    2-benzothienylmethyl   H                                                      2-benzofurylmethyl     H                                                      1,3,4-thiadiazol-2-ylmethyl                                                                          H                                                      1,3,4-oxadiazol-2-ylmethyl                                                                           H                                                      1H--tetrazol 1-ylmethyl                                                                              H                                                      α-aminobenzyl    pMB                                                      "                    2,2,2-trichloroethyl                                     "                    H                                                      α-amino-(4-hydroxybenzyl)                                                                      H                                                      α-amino-(3-methylsulfonylaminobenzyl)                                                          H                                                      α-hydroxybenzyl  H                                                      α-formyloxybenzyl                                                                              H                                                      α-carboxybenzyl  H                                                      α-carboxy-(4-hydroxybenzyl)                                                                    H                                                      α-sulfobenzyl    H                                                      α-[N.sup.3 --methyl-N.sup.3 --(2-chloro-                                                       H                                                      benzoyl)ureido]benzyl                                                         α-[N.sup.3 --(methylaminocarbonyl)N.sup.3 --methyl                                             H                                                      ureido]4-hydroxybenzyl                                                        α-(3-acetylimidazolidin-2-one-1-yl                                                             H                                                      carbonylamino)benzyl                                                          α-(3-methylsulfonylimidazolidin-2-                                                             H                                                      one-1-ylcarbonylamino)benzyl                                                  α-(4-ethylpiperizin-2-dione-1-yl                                                               H                                                      carbonylamino)benzyl                                                          α-(4-hydroxybenzamido)benzyl                                                                   H                                                      α-(3,4-dihydroxybenzamido)benzyl                                                               H                                                      ______________________________________                                    

and when R₁ is H the pharmaceutically acceptable non-toxic saltsthereof.

A preferred group of compounds of the invention are represented by theformula 1 when R is benzyl or phenoxymethyl. A further preferred groupare represented when R is R² --CH(Q--), and in particular, when Q isamino or substituted amino. Examples of such compounds are7β-(α-aminophenylacetylamino)-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylicacid,7β-[α-amino-α-(4-hydroxyphenyl)acetylamino]-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylicacid, 7β--amino-α-(3-hydroxy-4-chlorophenyl)acetylamino]-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylicacid, and the pharmaceutically acceptable salts thereof. The above-namedcompounds having an asymmetric carbon to which the amino group isattached in the 7-position side chain are preferably in the D-form.

The preferred compounds wherein Q is amino are prepared by employingknown acylation methods used in the β-lactam antibiotic art. Forexample, phenylglycyl chloride hydrochloride can be used to acylate thetrimethylsilyl ester of7-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylic acidin non-aqueous media in the presence of an acid-binding agent.

Also, the t-butyloxycarbonyl protected phenylglycine is converted to theactive derivative with a haloformic acid ester such as ethylchloroformate and the derivative used to acylate the7-amino-1-carbanucleus ester, e.g. the benzyl ester.

Another group of preferred compounds are represented by the formula 1when R is an oximino group represented by the formula ##STR23## Inparticular, compounds wherein the oximino group has the synconfiguration are preferred, especially when R³ is thiazolyl, e.g.2-aminothiazol-4-yl, 2-halothiazol-4-yl, and 2-methylthiazol-4-yl; andR₄ is C₁ -C₄ -alkyl or a carboxy-substituted C₁ -C₄ -alkyl group.

The compounds represented by the formula 1 wherein R₁ is hydrogen formsalts with inorganic and organic bases. Salts such as the alkali andalkaline earth metal salts, e.g. the sodium, potassium and calciumsalts, are formed with the respective alkali or alkaline earth metalhydroxides, carbamates and bicarbamates. Amine salts are formed withbasic amines such as benzylamine, dibenzylamine, ethanolamine,diethanolamine, propanolamine, procaine, and dicyclohexylamine. Thesesalt forms of the 1-carba-3-cephem compounds are useful in preparingpharmaceutically acceptable formulations of the antibiotics.

The 7-amino-1-carbacephalosporin nucleus compounds used in theabove-described N-acylation are obtained with 7-protected amino nucleuscompounds by removing the protecting group. This invention also providespreferred 7-amino- and 7-(protectedamino)-3-trifluoromethylsulfonyloxy-1-carba-3-cephem nucleus compoundsrepresented by the formula 2 ##STR24## wherein R⁰ is hydrogen or anamino-protecting group, and R₁ is hydrogen or a carboxy-protectinggroup. Amino-protecting groups represented by R⁰ are the conventionalprotecting or blocking groups used in the β-lactam antibiotic art forthe temporary protection of the amino group function while reactions atother sites in the molecule are carried out. Examples of suitableprotecting groups are formyl, trichloroacetyl, tribromoacetyl, trityl,an alkyl, cycloalkyl, or aryloxycarbonyl group such as ethoxycarbonyl,t-butyloxycarbonyl, trichloroethoxycarbonyl, cyclopentyloxycarbonyl,benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, anddiphenylmethoxycarbonyl; allyloxycarbonyl, a bicyclooxycarbonyl groupsuch as adamantyloxycarbonyl or bicycloheptyloxycarbonyl; or otherconventional amino-protecting group. Preferred amino-protecting groupsR⁰ are represented by the formula ##STR25## wherein R⁰ is C₁ -C₄ -alkyl,C₂ -C₄ alkenyl, C₃ -C₇ -cycloalkyl, benzyl, nitrobenzyl, halobenzyl ormethoxybenzyl.

Preferred amino-protecting groups are benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, and t-butyloxycarbonyl. carbonyl.

The 7-amino(or amino-protected)-3-trifluoromethylsulfonyloxy nucleuscompounds represented by the formula 2 are prepared with thecorresponding 3-hydroxy-1-carbacephalosporin obtained as described incopending application Ser. No. 755,982, filed July 17, 1985 U.S. Pat.No. 4,665,171. As described therein, an asymmetric process for thepreparation of 3-hydroxy-1-carbacephalosporins is provided. According tothe process, a 3β-[4(S)-aryloxazolidin-2-one-3-yl]azetidin-2-one isprepared and converted asymmetrically to a 7-amino-protected or7-acylamino 3-hydroxy-1-carbacephalosporin. The azetidinone-2 isrepresented by the formula ##STR26## wherein Ar is phenyl, C₁ -C₄alkylphenyl, halophenyl, C₁ -C₄ alkoxyphenyl, naphthyl, thienyl, furyl,benzothienyl, or benzofuryl; R is phenyl, C₁ -C₄ alkylphenyl, C₁ -C₄alkoxyphenyl, or halophenyl; Y is --CH═CH-, or --CH₂ -CH₂ -; and R' isphenyl, C₁ -C₄ alkylphenyl, C₁ -C₄ alkoxyphenyl, halophenyl, furyl ornaphthyl.

Preferred azetidinones are represented by the formula 1 wherein Ar and Rare phenyl or substituted phenyl, and R' is phenyl, substituted phenyl,or furyl. Examples of such preferred compounds are1-benzyl-3β-[4(S)-phenyloxazolidin-2-one-3-yl]-4β-styrylazetidin-2one,1-benzyl-3β-[4(S)-phenyloxazolidin-2-one-3-yl]-4β-(3-methoxystyryl)azetidin-2-one,and1-benzyl-3β-[4(S)-phenyloxazolidin-2-one-3-yl-4β-[2-(2-furyl)ethenyl]-azetidin-2-one.

The azetidinones are obtained by the cyclo-addition of a4(S)-aryloxazolidin-2-one-3-ylacetyl halide and an imine formed with abenzylamine and a 3-arylacrolein. The acid halide is converted in situwith a trialkylamine to the corresponding homochiral ketene. The keteneand imine upon cycloaddition provide the azetidinone. Alternatively, theketene can be generated with the anhydride of the oxazolidinone aceticacid and trifluoroacetic acid, or with phosphoryl chloride or phosphorylbromide. The cycloaddition reaction is a key step in the asymmetricprocess for the preparation of 1-carba-(1-dethia)cephalosporins.

The 4(S)-aryloxazolidin-2-one-3-ylacetyl halide employed in thecyclization is obtained with an L-arylglycine represented by the formula1a ##STR27## wherein Ar has the same meanings as defined above. Thepreparation is illustrated in the following reaction scheme. ##STR28##

In the above scheme "alk" refers to C₁ -C₄ alkyl e.g. methyl, ethyl,n-propyl, and t-butyl; X refers to halogen, preferably chloro or bromo;X' is chloro, bromo, trifluoroacetoxy, or -OP(═O)X₂ wherein X ishalogen; and Ar has the same meanings as previously defined.

In carrying out the preparation of the 4-aryloxazolidinone 4a theL-arylglycine is first converted to the carbamate 2a. The arylglycine isdissolved in aqueous base by utilizing only the amount of base needed toform the soluble salt plus a small excess. The solution is cooled to atemperature between about 0° C. and about 10° C. and non-stoichiometricamounts of the haloformate are added in several portions with stirring.Additional base is added to redissolve the arylglycine and additionalhaloformate is added portionwise with stirring. This process is repeatedin the cold until an excess of the stoichiometric amount of haloformatehas been added and carbamate formation is completed. The reaction ispreferably carried out as rapidly as possible. Bases such as the alkalimetal hydroxides, e.g. sodium hydroxide and potassium hydroxide are bestused. Preferably 3N sodium hydroxide is used. The L-carbamate derivative2a is recovered from the reaction mixture by acidification andextraction of the precipitated carbamate with a water immiscible solvente.g. a halogenated hydrocarbon solvent such as dichloromethane.

The L-carbamate 2a is reduced with excess borane-dimethylsulfide intetrahydrofuran at a temperature between about 20° C. and about 40° C.to provide the L-alcohol 3a. The borane-dimethylsulfide reagent is addedto a solution of the carbamate acid in tetrahydrofuran cooled to about0° C. and the mixture is stirred a the temperature range, convenientlyat room temperature, for about 10 hours to 20 hours. The excess boraneis destroyed by quenching the mixture with water and 3a is recovered byconcentrating the mixture by evaporation, diluting the concentrate withmore water if necessary, and extracting 3a with a water immisciblesolvent such as methylene chloride. The recovered 3a is of sufficientpurity to use directly in the cyclization to 4a, however, it may befurther purified prior to use by recrystallization.

The L-alcohol 3a is then cyclized to the (S)-4-aryloxazolidin-2-one (4a)in an inert solvent with n-butyllithium or an alkali metal alkoxide suchas lithium or sodium ethoxide. n-Butyllithium is the preferred base andis generally used in less than the stoichiometric amount. The reactionis carried out for from 2 to 8 hours at a temperature between about 25°C. and about 65° C. and preferably at about 55° C. Suitable inertsolvents are tetrahydrofuran, 1,2-dimethoxyethane and like ethers. Aftercompletion of the cyclization, the reaction mixture is treated withacetic acid in an amount corresponding to the amount of base used, andis concentrated. The oxazolidin-2-one-(4a) is recovered from theconcentrate by extraction with a suitable organic solvent such asmethylene chloride, chloroform, or trichloroethane.

The (S)-4-aryloxazolidin-2-one (4a) is N-alkylated with a haloaceticacid ester, the ester deesterified, and the acid converted to the acylhalide 5a.

The alkylation of 4a with the haloacetic acid ester is carried out indimethylformamide or tetrahydrofuran with sodium hydride to provide the(S)-4-aryloxazolidin-2-one-3-ylacetic acid ester. The haloacetic acidester is represented by the formula X-CH₂ COOalk in the foregoingreaction scheme, wherein X is chloro or bromo and alk is C₁ -C₄ alkyl.Preferably, alk is t-butyl or ethyl. Examples of haloacetic acid estersare t-butyl bromoacetate, ethyl bromoacetate, methyl chloroacetate,t-butyl chloroacetate, methyl bromoacetate, isopropyl bromoacetate, andlike esters. Preferred halo esters are t-butyl bromoacetate and ethylbromoacetate.

The deesterification of the oxazolidinone acetic acid ester is achievedby standard deesterification procedures. For example, the t-butyl estergroup is removed upon treatment of the ester with trifluoroacetic acidwhile other lower alkyl esters such as the ethyl ester can besaponified.

The oxazolidinone acetic acid is converted to the acid halide (5a,X'=halogen), preferably the acid chloride, the anhydride formed withtrifluoroacetic acid (X'═OCOCF₃), or with a phosphoryl halide(X'═-O-P(═O)X₂). The acid halide, preferably the chloride, is apreferred source of the ketene for use in the subsequent cyclo-additionreaction. The acid chloride is obtained for example with oxalyl chloridein an inert solvent such as benzene, toluene, or xylene. Otherconventional acid halide forming reagents may be used.

The (S)-4-aryloxazolidin-2-one-3-ylacetyl halide or anhydride is thefunctionalized form of the chiral auxiliary moiety used to form theβ-lactam ring of the azetidinone intermediates represented by the aboveformula.

The acetyl halide (5a) is allowed to react with the imine formed with abenzylamine and a 3-arylacrolein to form the1-benzyl-3β-[(S)-4-aryloxazolidin-2-one-3-yl]yl[-4β-(2-arylvinyl)azetidinone(formula 1, Y=--CH═CH). A minor amount of isomeric cycloaddition productis also formed. The cycloaddition reaction is illustrated in thefollowing reaction scheme ##STR29## wherein R, R' and Ar have the samemeanings as defined above.

The reaction is carried out at a temperature between about -78° C. andabout 25° C. in an inert organic solvent, such as methylene chloride,chloroform, toluene, or a di- or trichloroethane in the presence of atri-(C₁ -C₄ alkyl)amine. A solution of the imine (6a) is added to asolution of 5a in an inert solvent containing the tri-(C₁ -C₄alkyl)amine in an amount in excess of the stoichiometric amount. Thetri-(C₁ -C₄ alkyl)amine is added to the solution of 5a prior to additionof the imine 6a. The acid derivative 5a and the amine are mixed at atemperature between about -80° C. and about -50° C. to form in situ theketene. The imine 6a is then added to form the azetidinone.Conveniently, the solvent for the imine is the solvent in which it wasprepared as described hereinbelow. Such solvents as benzene, toluene,and the xylenes are suitable. Following the addition of the imine, thereaction is warmed and maintained at about 0° C. for from 2 to 4 hours.The mixture of the major isomer and the minor isomer is recovered fromthe reaction mixture as follows. The reaction mixture is diluted with awater immiscible organic solvent such as methylene chloride orchloroform and is first washed with a weak acid such as tartaric acid orcitric acid followed by a wash with saturated aqueous alkali metalbicarbonate. After drying, the washed mixture is evaporated to dryness.Most often the major isomer can be crystallized from the residue fromethyl acetate-hexanes (ca 30% hexanes by volume). Alternatively, themajor isomer can be separated from the minor isomer by chromatographyover silica by using step-wise elution or gradient elution. Step-wiseelution with ethyl acetate-methylene chloride with a percentage ethylacetate by volume of from ca 20% will generally elute the azetidinonewhile increased polarity (ca 40%-50% ethyl acetate by volume) will elutethe minor component. After chromatography the azetidinone can berecrystallized to enhance its purity.

The imine 6a employed in the cycloaddition is obtained by condensing a3-arylacrolein with benzylamine or a substituted benzylamine in asuitable solvent. The water produced during the reaction is removedeither by using a drying agent or by azeotropic distillation. A smallexcess over the stoichimetric amount of the acrolein is preferably used.Drying agents such as magnesium sulfate or molecular sieves aresuitable. Organic solvents such as diethyl ether or an aromatichydrocarbon such as benzene or toluene can be employed.

The condensation to form the imine proceeds rapidly at a temperaturebetween about 25° C. and 65° C. in the presence of a drying agent orduring azeotropic removal of water.

Examples of 3-arylacroleins which can be used are represented by theformula ##STR30## wherein R' is phenyl, C₁ -C₄ alkylphenyl, C₁ -C₄alkoxyphenyl, halophenyl, furyl or naphthyl. Examples of such aldehydesare cinnamaldehyde, 4-methylcinnaldehyde, 3-ethylcinnamaldehyde,4-ethoxycinnamaldehyde, 3-methoxycinnamaldehyde,3-t-butyloxycinnamaldehyde, 3-ethoxycinnamaldehyde,3-bromocinnamaldehyde, 2-(2-furyl)acrolein, 2-(2-naphthyl)acrolein, andlike aldehydes.

Examples of benzylamines useful in the imine formation are benzylamineand the C₁ -C₄ alkyl, C₁ -C₄ alkoxy, and halo-substituted benzylaminessuch as 4-methylbenzylamine, 3-chlorobenzylamine,3,4-dichlorobenzylamine, 4-methoxybenzylamine, 2-bromobenzylamine,3-ethylbenzylamine, 3,4-dimethylbenzylamine, 2,4-dimethylbenzylamine,4-chloro-3-methylbenzylamine, 4-isopropylbenzylamine,4-t-butylbenyylamine, and the like.

The imine 6a can be employed in the cycloaddition reaction without priorisolation. For example, the reaction mixture in which the imine isprepared may be used directly in the cycloaddition.

The azetidinone represented by the formula wherein Y is --CH═CH-- and R'is an m-alkoxyphenyl group, is a valuable intermediate in a processprovided by this invention for the asymmetric preparation of1-carbacephalosporins. In particular the process comprises thepreparation of 1-carba-3-hydroxy-3-cephem-4-carboxylic acid esters.

According to the process the (S)-4-aryloxazolidin-2-one-3-ylacetylhalide (5a) is reacted in the cycloaddition reaction described abovewith the imine (6a), formed with a benzylamine and am-alkoxycinnamaldehyde, to provide the azetidinone represented by theabove formula wherein Y is --CH═CH-- and R' is a m-C₁ -C₄ alkoxyphenylgroup. The azetidinone is hydrogenated to the corresponding4β-[2-(m-alkoxyphenyl)ethyl]-azetidinone, and the latter is reduced withlithiumammonia in the presence of t-butyl alcohol to effect reduction ofthe phenyl ring, removal of the chiral auxiliary and the 1-benzyl groupto provide a3β-amino-4β-[2-(5-alkoxycyclohex-1,4-dienyl)ethyl]azetidinone. The3-amino group of the azetidinone is protected with a conventionalamino-protecting group and the 3β-protected-aminoazetidinone issubjected to ozonolysis to yield the β-keto ester C₁ -C₄ alkyl5-[3β-(protected amino)azetidin-2-one-4β-yl]-3-oxopentanoate.

The β-keto ester ozonolysis product is converted to the α-diazoderivative and the diazo derivative is cyclized with Rhodium II toprovide the 3-hydroxy-1-carbacephalosporin ester.

The process is illustrated in the following reaction scheme. ##STR31##

It will be appreciated with reference to the foregoing reaction schemethat the imine 6a is structurally selective in the process. Them-alkoxyphenyl group of the imine ultimately provides the alkylβ-ketoester 9a via ozonolysis of the 5-alkoxycyclohexa-1,4-diene 8awhich in turn is provided by the lithium in ammonium reduction of theazetidinone wherein Y=--CH₂ --CH₂ --.

According to this process the azetidinone (Y=--CH═CH--) is hydrogenatedover a palladium catalyst such as a supported palladium catalyst, e.g.5% or 10% palladium on carbon, barium carbonate, or other suitablesupport. The reduction can be carried out at atmospheric pressure, or atsomewhat elevated pressures, in an inert solvent at room temperature.Inert solvents such as methylene chloride, di- or trichloroethane,tetrahydrofuran, methyl alcohol, ethyl alcohol, or ethyl acetate may beused.

The 4β-[2-(m-alkoxyphenyl)ethyl]azetidinone is reduced to the3β-amino-4β-[2-(5-alkoxycyclohex-1,4-dienyl)ethyl]azetidin-2-one (7a)with lithium in liquid ammonia containing t-butyl alcohol. The reductionis carried out at a temperature between about -30° C. and about -90° C.and preferably at between about -70° C. and about -80° C. The reductionis carried out by dissolving lithium in liquid ammonia and cooling thesolution to about -50° C. and about -90° C. An excess of t-butyl alcoholis added followed by the addition of a solution of the azetidinone in aninert solvent. The solution of the azetidinone may contain t-butylalcohol as a cosolvent. Suitable solvents for the azetidinone includetetrahydrofuran, dimethoxyethane, or like solvent.

After the solution of the azetidinone is added, the reduction mixture isstirred for about 30 minutes to about 2 hours. On small laboratory sizereactions, the reduction is allowed to stir in the cold for about 30minutes while with large scale reductions in manufacture somewhat longerreduction time may be required for complete reduction to the diene 7a.

The reduction effects the removal of the chiral auxiliary moiety,incorporated via the cyclo-addition with 6a, leaving the 3-amino group.The reduction also effects removal of the 1-benzyl or 1-substitutedbenzyl group.

The 3-aminoazetidinone 7a can be isolated from the reduction mixture andused in the next step after amino group protection as shown in thereaction scheme. Alternatively, and preferably in the process context,7a is acylated in the same reaction vessel to provide the acylatedaminoazetidinone 8a. Following the reduction the reaction mixture istreated with sufficient benzene to discharge the blue color of themixture. Ammonium acetate is added to the mixture and the bulk of theammonia is distilled off. The solvent and any remaining ammonia areevaporated. The residue 7a is treated with a water miscible organicsolvent such as tetrahydrofuran and the mixture or solution is acidifiedto a pH between about 7 and about 9. The solution of 7a is then treatedwith an acylating agent to provide the3β-acylamino-4β-[2-(5-alkoxycyclohex-1,4-dienyl)ethyl]azetidinone 8a.The 3β-amino group is acylated to protect its integrity during thesubsequent ozonolysis step in the process.

The acylating agent may be formed with any carboxylic acid, the acylresidue of which is stable in the subsequent ozonolysis step of theprocess. The carboxylic acid can be for example an alkylcarboxylic acidsuch as acetic acid, propionic acid, butyric acid and the like; anarylcarboxylic acid such as benzoic acid, napthoic acid, which may beoptionally substituted by lower alkyl, lower alkoxy, or halogen; or anarylacetic acid such as phenylacetic acid, phenoxyacetic acid,phenylthioacetic acid, and such acids optionally substituted. Thedesired carboxylic acid for use in the acylation is converted to anactive derivative such as the acid chloride, acid anhydride or an activeester formed with a haloformate such as a C₁ -C₄ alkyl chloroformate,e.g. ethyl chloroformate and iso-butyl chloroformate.

The acylating agent also can be an aryloxycarbonyl halide such asbenzyloxycarbonyl chloride or p-nitrobenzyloxycarbonyl chloride.

Preferred acylating agents are represented by the formula ##STR32##wherein R₁ is C₁ -C₆ alkyl; a phenyl group ##STR33## wherein a and a'independently are hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy or halogen; agroup represented by the formula ##STR34## wherein Z is O or S, m is 0or 1, and a and a' have the same meanings as defined above; or R₁ is R°₁O wherein R°₁ represents C₁ -C₄ alkyl, C₅ -C₇ cycloalkyl, benzyl,nitrobenzyl, methoxybenzyl, or halobenzyl; and W is chloro, bromo, or ananhydride forming group represented by the formula ##STR35## wherein R₁has the same meanings as defined above.

Examples of acyl halides represented by the above formula are acetylchloride, acetyl bromide, butyryl chloride, propionyl chloride, benzoylchloride, 4-chlorobenzoyl chloride, 4-methylbenzoyl chloride,phenoxyacetyl chloride, 4-chlorophenoxyacetyl chloride, phenylacetylchloride, 3-ethylphenylacetyl bromide, phenylmercaptoacetyl chloride,4-chlorophenylmercaptoacetyl chloride, benzyloxycarbonyl chloride,cyclohexyoxycarbonyl chloride, cyclopentyloxycarbonyl chloride,ethoxycarbonyl chloride, and the like.

Examples of anhydrides represented by the above formula are benzoic acidanhydride, phenoxyacetic acid anhydride, phenylacetic acid anhydride,p-chlorophenoxyacetic acid anhydride, phenylmercaptoacetic acidanhydride, di-t-butyl dicarbonate, dibenzyl dicarbonate,di-(p-nitrobenzyl) dicarbonate, di-ethyl dicarbonate, di-cyclohexyldicarbonate, and like anhydrides.

The N-acylated reduction product 8a is recovered from the mixture byextraction and is purified by chromatography over silica.

The 3-acylaminoazetidinone 8a is then converted to the β-keto ester 9aby ozonolysis. The ozonolysis is preferably carried out in 50% methylalcohol in dichloromethane or other suitable solvent mixture, at atemperature between about -5° C. and about -80° C. The ozone is passedinto the solution of the diene 8a until the reaction is complete. Theozone is most conveniently obtained from a conventional ozone generatorin a stream of air. The completion of the ozonolysis may be determinedby the use of a diene indicator such as solvent red (Sudan III, AldrichChemical Company). Following completion any ozonide and excess ozone isdestroyed in the cold with dimethyl sulfide or other suitable reducingagent such as a sulfite or phosphite and the product 9a is recoveredfrom the mixture. For example, the reaction mixture is allowed to warmto room temperature, is poured into brine and the product is extractedwith a water immiscible solventssuch as methylene chloride. The β-ketoester 9a may be further purified by chromatography over silica.

The β-keto ester 9a is then converted to the7-acylamino-1-carba(1-dethia)-3-hydroxy-3-cephem ester 11a via diazocompound 10a, and cyclization of the diazo ester to the1-carbacephalosporin with rhodium II. ##STR36##

The β-keto ester 9a is best converted to the diazo ester 10a in an inertsolvent such as acetonitrile, dichloromethane, trichloroethane, or thelike, with p-toluenesulfonyl azide (tosyl azide) in the presence of ahindered tertiary amine, e.g. diisopropylethylamine. The reaction iscarried at conveniently at room temperature. Generally the tosyl azideis used in an excess of the stoichiometric amount while the amine isused in an amount of about one-fourth of the stoichiometric amount. Thediazo ester is recovered from the reaction mixture by partitioning themixture between a water immiscible solvent such as methylene chlorideand brine containing some tartaric acid or citric acid. The diazo esteris obtained in purified form from the extract via chromatography oversilica and recrystallization.

The ester moiety "alk" of 10a becomes the ester group of the1-carbacephalosporin 11a upon cyclization as shown in the reactionscheme. Ester groups such as the lower n-alkyl groups e.g. methyl, andethyl, are less readily removed form the carboxy function than othergroups. From a synthetic point of view, it may be desirable to form a1-carbacephalosporin 11a wherein the ester group is a conventionalcarboxy-protecting group more readily removed than methyl or ethyl. Afurther aspect of the copending application provided a process for thetransesterfication of the ester group (alk) of 10a to diazo ester 10b asshown below. ##STR37## wherein R₁ and alk have the previously definedmeanings and R₂ is allyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl,β-tri(C₁ -C₄ alkyl)silylethyl, benzyl, C₁ -C₄ alkylbenzyl, C₁ -C₄alkoxybenzyl, nitrobenzyl, or chlorobenzyl.

The process is carried out by mixing an excess of the alcohol, R₂ OH,with titanium tetraisopropoxide and removing isopropyl alcohol byevaporation. The diazo ester, 10a, is added to the solution of theTi(OR₂)₄ in excess alcohol, and an inert solvent if necessary, and thesolution is maintained at a temperature between about 25° C. and about45° C. until transesterification is complete.

Inert solvents which may be used are, for example, methylene chloride,di- or trichlorethane, chloroform, acetonitrile, tetrahydrofuran, ordioxane. When benzyl alcohol is used in the process to form the R₂ estergroup it also may serve as a solvent for the process.

The diazo ester 10a or the diazo ester 10b obtained via thetransesterification process is then cyclized to 1-carbacephalosporin llawith rhodium II acetate in chloroform at the reflux temperature. Thereaction is heated for about 15 minutes to about one hour and the7-acylamino-3-hydroxy-1-carba(1-dethia)-3-cephem-carboxylic acid esteris recovered as such from the reaction mixture or is converted to aderivative which is then isolated.

The 3-hydroxy 1-carbacephalosporin ester may be recovered from thereaction mixture by first diluting the mixture with water or brine,acidifying the mixture, and then extracting the mixture with a solventsuch as ethyl acetate or methylene chloride. The extract is washed,dried and evaporated to provide the product. The product may be furtherpurified by chromatography and recrystallization.

In a preferred embodiment of the process L-phenylglycine (1a, Ar=phenyl)is converted to the ethylcarbamate with ethyl chloroformate, thecarbamate acid is reduced with borane-dimethyl sulfide toL-1-ethoxycarbonylamino-1-phenylethanol (3a, alk=ethyl), and thephenylethanol is cyclized with n-butyllithium to(S)-4-phenyloxazolidin-2-one 4a. The latter is converted to 5a viaalkylation with ethyl bromoacetate, saponification, and treatment of theacid with oxalyl chloride.

The (S)-4-phenyloxazolidin-2-one-3-ylacetyl chloride is condensed withthe imine formed with benzylamine and m-methoxycinnamaldehyde (form 6a,alk=methyl, R=phenyl) to form the azetidinone 1, Ar=phenyl, alk=methyl).Catalytic reduction of 1 over 5% Pd-C provides azetidinone, (Y=CH₂ --CH₂--) which on reduction in lithium in liquid ammonia and t-butyl alcoholyields the 3-aminoazetidinone (7a, alk=methyl). Without isolation, the3-aminoazetidinone is acylated with di-(t-butyl) dicarbonate to form the3-t-butyloxycarbonylaminoazetidinone (8a, R₁ =t-butyloxy, alk=methyl).Ozonolysis of the 3-t-BOC amino protected diene product in 50% methylalcohol in dichloromethane provides the β-keto methyl ester 9a. Theβ-keto methyl ester is reacted in acetonitrile with tosyl azide in thepresence of diisopropylethylamine to provide the diazo methyl ester(10a, R₁ = t-butyloxy, alk=methyl). The transesterification of the diazomethyl ester to the corresponding benzyl ester is carried out in excessbenzyl alcohol with titanium tetra-isopropoxide with heating at about36° C. for 42 hours. The diazo benzyl ester is treated in refluxingchloroform with rhodium (II) acetate to provide benzyl7β-(t-butyloxycarbonylamino)-3-hydroxy-1-carba(1-dethia)-3-cephem-4-carboxylate.

The 3-trifluoromethylsulfonyloxy-1-carba-3-cephem compounds representedby the formula 1 wherein A and R₁ are other than hydrogen are useful ina process for preparing 3-chloro or 3-bromo-1-carba-3-cephem compounds.According to the process a 3-triflate ester represented by the formula 3##STR38## is reacted in an aprotic polar solvent at a temperaturebetween about 60° C. and about 95° C. with a lithium halide, LiX", toform a 3-halo-1-carba-3-cephem compound represented by the formula 4##STR39## wherein A' is an amino-protecting group or an acyl group RCOwherein R has the same meanings as defined for formula 1, R₂ is acarboxy-protecting group, and X" is chloro or bromo.

Aprotic polar solvents which can be used are dimethylformamide,dimethylacetamide, N-methylpyrrolidone, acetonitrile, and like solvents.Dimethylformamide is a preferred solvent.

Preferably the process is carried out at a temperature between about 75°C. and about 85° C. with an excess of the stoichiometric amount of thelithium halide salt.

The carboxy-protecting ester group R₂ (formula 3) is a conventionalcarboxy-protecting ester group and preferably one which is notsterically hindered. Examples of such groups are benzyl and substitutedbenzyl groups such as 4-methoxybenzyl, 4-nitrobenzyl, 4-methylbenzyl,3,5-dimethylbenzyl, and 4-chlorobenzyl; silyl esters such astrialkylsilyl ester, e.g. trimethylsilyl; and halo-substituted alkylesters such as 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, and2-iodoethyl. Hindered ester groups such as the t-butyl ester groupappear to inhibit the displacement of the CF₃ SO₃ group by the halideion owing to their bulk resulting in lower yields of the 3-halo product.A preferred ester group is the benzyl or a substituted benzyl estergroup.

Following completion of the process the 3-halo-1-carba-3-cephem ester isrecovered from the reaction mixture by conventional isolation methodsand is purified by chromatography.

During the process any amino groups present in the starting material aredesirably protected. For example, when in the compound represented bythe formula 1 Q is an amino group or, when there is an amino oraminomethyl substituent attached to the phenyl ring when R is asubstituted benzyl or phenyl group, an amino-protected derivative isdesirably used on the starting material in the process. In an example ofthe process, benzyl7β-phenoxyacetylamino-3-trifluoromethyl-sulfonyloxy-1-carba-3-cephem-4-carboxylateis dissolved in dimethylformamide and an excess (3-4 molar excess) oflithium chloride is added. The solution is heated to a temperature ofabout 80° C. with stirring for about 5-6 hours. The progress of thereaction can be followed by thin layer chromatography of a small aliquotof the reaction mixture removed from time to time. When the reaction iscompleted the mixture is diluted with a water immiscible organicsolvent, washed with water, dried, and evaporated. The crude product,benzyl 7β-phenoxyacetylamino-3-chloro-1-carba-3-cephem-4-carboxylate, ispurified by chromatography, e.g. over silica gel.

The following Examples are provided to further illustrate the invention.

Preparation of benzyl7β-(t-butyloxycarbonylamino)-3-hydroxy-1-carba-3-cephem-4-carboxylate(S)-4-Phenyloxazolidin-2-one

To a stirred, 0° C. solution of L-phenylglycine (25.3 g, 167.4 mmol) in60 mL of 3N aqueous NaOH was added ethyl chloroformate (8 mL) in severalportions. Additional 3N aqueous NaOH (35 mL) was added to redissolve theprecipitated phenylglycine, followed by ethyl chloroformate (4 mL). Thisprocess was continued with 3N aqueous NaOH (65 mL) and ethylchloroformate (8 mL, total of 20 mL, 209 mmol) over a period of ca. 10minutes. After stirring for 1 hour at 0° C. the solution was acidifiedwith 6 M H₂ SO₄, and the precipitated carbamate was extracted into 8%isopropanol in dichloromethane (2×300 mL). The combined organic layerswere dried (Na₂ SO₄) and concentrated to afford 37.3 g ofN-ethoxycarbonyl L-phenylglycine as a white solid. The carbamate wasdissolved in 170 mL of THF, cooled to 0° C., treated withborane-dimethylsulfide (33.5 mL of a 10 M solution), and stirred at roomtemperature for 17 hours. Excess borane was cautiously quenched withwater (100 mL), and the bulk of the THF removed under reduced pressure.The white slurry was diluted with additional water (350 mL) and thenextracted with dichloromethane (2×500 mL). The combined organic layerswere washed with 100 mL of saturated aqueous NaHCO₃, dried (Na₂ SO₄),and concentrated to give 27.4 g of(S)-2-ethoxycarbonylamino-2-phenylethanol as a white solid. The crudealcohol was dissolved in 200 mL of THF, cooled to 0° C., and treatedwith n-butyllithium in hexane (6 mL of a 2 M solution). After heating at55° C. for 6 hours, the solution was treated with acetic acid (1 ml) andconcentrated. The residue was dissolved in dichloromethane (300 mL),washed with 100 mL of brine, dried (Na₂ SO₄), and concentrated to awhite solid. Recrystallization from toluene gave 17.14 g (63%) of(S)-4-phenyloxazolidin-2-one; mp 132°-133° C.; [α]_(D) ²⁰ +49.5° (c=2.1,CHCl₃); IR (CHCl₃) 3460, 3020, 1760, 1500, 1480, 1460, 1400, 1230 cm⁻¹ ;¹ HNMR δ7.45-7.30 (m, 5, ArH), 6.42 (br s, 1, NH), 4.96 (br t, 1, J=7.8Hz, OCH₂ CH), 4.72 (t, 1, J=8.6 Hz, one of OCH₂ CH), 4.17 (dd, 1, J=6.7,8.7 Hz; one of OCH₂ CH).

Anal. Calcd for C₉ H₉ NO₂ : C, 66.24; H, 5.56. Found: C, 66.16; H, 5.62.

(S)-4-Phenyloxazolidin-2-one-3-ylacetic acid

To a stirred, 0° C. solution of (S)-4-phenyloxazoldin-2-one (1.07 g,6.54 mmol) in 15 mL of THF was added sodium hydride (0.32 g of a 60% oildispersion, 8.0 mmol). When gas evolution had ceased (ca. 10 minutes),ethyl bromoacetate (0.87 mL, 7.8 mmol) was added. After 2 hours at 0°C., the mixture was treated with 50 mL of 2N aqueous NaOH, stirredrapidly for 1 hour at room temperature, and then partitioned betweenhexane (50 mL) and water (50 mL). The aqueous layer was separated,acidified with 6 M aqueous H₂ SO₄, and extracted with dichloromethane(2×200 mL). The combined organic phases were dried (Na₂ SO₄) andconcentrated to a thick oil, which was dissolved in 4 mL of warmtoluene, seeded, and allowed to crystallize overnight; filtration gave1.33 g (92%) of (S)-4-phenyloxazolidin-2-one-3-ylacetic acid: mp106°-108° C.; [α]_(D) ²² +173° (c=2.0, CHCl₃); IR (CHCl₃) 3500-2500 (v.br), 1760 (br), 1480, 1460, 1430, 1230 cm₋₁ ; ¹ H NMR δ11.2 (br s, 1,COOH), 7.47-7.25 (m, 5, ArH), 5.05 (t, 1, J=8.4 Hz, OCH₂ CH), 4.72 (t,1, J=8.8 Hz, one of OCH₂ CH), 4.32 (d, 1, J=18.4 Hz, one of NCH₂), 4.17(t, 1, J=8.4 Hz, one of OCH₂ CH), 3.41 (d, 1, J=18.4 Hz, one of NCH₂).

Anal. Calcd for C₁₁ H₁₁ NO₄ : C, 59.72; H, 5.01. Found: C, 59.83; H,5.00.

(S)-4-phenyloxazolidin-2-one-3-ylacetyl chloride

A 250 mL round bottom flask fitted with a reflux condensor and a CaSO₄drying tube was charged with (S)-4-phenyloxazolidin-2-one-3-ylaceticacid (5.3 g, 23.96 mmol) and 60 mL of toluene. The suspension wastreated with oxalyl chloride (3.2 mL, 36.7 mmol) and stirred at 60° C.for 3 hours. At this point gas evolution had ceased and the reaction washomogeneous. Removal of solvent under reduced pressure afforded thetitle acid chloride as a thick oil.

Preparation of imine formed from benzylamine and 3-methoxycinnamaldehyde

To a solution of 3-methoxycinnamaldehyde (4.27 g, 26.33 mmol) in 40 mLof toluene was added benzylamine (2.73 mL, 25.01 mmol). The solution waswarmed briefly to ca. 40° C., and upon cooling became cloudy fromreleased water. Argon flushed 4A molecular sieves (18 g, freshlyactivated) were added and the mxture was allowed to stand at roomtemperature for 16 hours. This solution of imine was used directly inthe subsequent cyclization.

Formation of1-benzyl-3β-[(S)-4-phenyloxazolidin-2-one-3-yl]-4β-(3-methoxystyryl)azetidin-2-one

The oxazolidinone acid chloride was dissolved in dichloromethane (70mL), cooled to -78° C., and treated with triethylamine (5.0 mL, 35.9mmol). A fine, heavy precipitate formed over 15 minutes. To this mixturewas added, via cannula, the toluene solution of the imine prepared asdescribed above. The sieves from the imine solution were washed withdichloromethane (2×10 mL), and each wash added to the reaction. The coldbath was removed, the reaction warmed and maintained at 0° C. for 2hours. The mixture was poured into 200 mL of dichloromethane, washedwith 0.5 M tartaric acid and saturated aqueous NaHCO₃ (50 mL each),dried (Na₂ SO₄), and concentrated to a reddish oil. Crystallization fromca. 150 mL of 30% hexanes in ethyl acetate gave 6.87 g of the titlecompound as white needles. Chromatography of the mother liquor on 170 gof silica with 20% ethyl acetate in dichloromethane gave an additional1.9 g of the azetidinone (total 8.77 g, 80%). The minor isomer wasobtained by further elution with 40% ethyl acetate in dichloromethaneand was then purified by chromatography on silica with 30% hexanes inethyl acetate.

Major isomer the title compound: mp 142°-143° C.; [α]_(D) ²² +46.4°(c=1.0, CHCl₃); IR CHCl₃) 3020, 1760, 1600, 1410 cm⁻¹ ; ¹ H NMR (CDCl₃)δ7.45-6.75 (m, 14, ArH), 6.45 (d, 1, J=16 Hz, ArCH═CH), 5.81 (dd, 1,J=16, 8.9 Hz, ArCH═CH), 4.88 (dd, 1, J=8.9, 7.4 Hz, OCH₂ CH), 4.61 (t,1, J=8.9 Hz, one of OCH₂ CH), 4.55 (d, 1, J=5 Hz, C₃ H), 4.53 (d, 1,J=14.7 Hz, one of ArCH₂), 4.23-4.12 (m, 3, one of ArCH₂, one of OCH₂ CH,C₄ H), 3.82 (s, 3, OCH₃).

Anal. Calcd for C₂₈ H₂₆ N₂ O₄ : C, 73.99; H, 5.77. Found: C, 74.06; H,5.74.

By using the method described in Example 1, the imine prepared frombenzylamine and cinnamaldehyde, and4(S)-phenyloxazolidin-2-one-3-ylacetyl chloride there was prepared1-benzyl-3β-[4(S)-phenyloxazolidine-2-one-3-yl]-4β-styrylazetidine-2-one:mp 186.5°-187.5° C.; [α]_(D) ²² =+56.9° (c=1.7, CHCl₃); IR (CHCl₃) 3010,1760, 1500, 1460, 1410 cm⁻¹ ; ¹ H NMR (CDCl₃) δ7.45-7.10 (m, 15, ArH),6.48 (d, 1, J=16 Hz, CH═CH--Ar), 5.87 (dd, 1, J=9, 16 Hz, CH═CH--Ar),4.88 (dd, 1, J=7.4, 8.9 Hz, OCH₂ CH), 4.61 (t, 1, J=8.9, one of OCH₂CH), 4.55 (d, 1, J=16 Hz, one of ArCH₂), 4.54 (d, 1, J= 4.7 Hz, C-3 H,overlaps with doublet at 4.55), 4.21 (dd, 1, J=4.7, 9.0 Hz, C-4 H), 4.17(dd, J=7.4, 8.9 Hz, one of OCH₂ CH), 4.14 (d, 1, J=16 Hz, one of ArCH₂).

Anal. Calcd. for C₂₇ H₂₄ N₂ O₃ : C, 76.39; H, 5.70. Found: C, 76.53; H,5.69.

By using the method described in Example 1, the imine prepared frombenzylamine and 3-(2-furyl)-acrolein was condensed with4(S)-phenyloxazolidin-2-one-3-ylacetyl chloride to provide1-benzyl-3β-[4(S)-phenyloxazolidine-2-one-3-yl]-4β-[2-(2-furyl)ethenyl]-azetidine-2-one:mp 181°-182° C.; [α]_(D) ²⁰ =+13.6° (c=1.6, CHCl₃), IR (CHCl₃) 3020,1760, 1660, 1500, 1460, 1410 cm⁻¹ ; ¹ H NMR (CDCl₃) δ7.45-7.07 (m, 11,ArH), 6.39 (dd, 1, J=1.8, 3.3 Hz, OCH═CH), 6.27 (d, 1, J=16 Hz,N--CH--CH═CH), 6.25 (d, 1, J=3.3 Hz, O--C═CH), 5.75 (dd, 1, J=16, 8.9Hz, N--CH--CH═CH), 4.91 (dd, 1, J=8.8, 7.4 Hz, OCH₂ CH), 4.65 (t, 1,J=8.9 Hz, one of OCH₂ CH), 4.61 (d, 1, J=15 Hz, one of ArCH₂), 4.55 (d,1, J=4.8 Hz, C-3 H), 4.20 (dd, 1, J=7.4, 8.8 Hz, one of OCH₂ CH), 4.11(dd, 1, J=4.8, 8.9 Hz, C-4 H), 4.02 (d, 1, J=15 Hz, one of ArCH₂).

Anal. Calcd. for C₂₅ H₂₂ N₂ O₄ : C, 72.44; H, 5.35. Found: C, 72.44; H,5.41.

1-Benzyl-3β-(S)-4-phenyloxazolidin-2-one-3-yl]-4β-[2-(3-methoxyphenyl)ethylazetidin-2-one

The 3-methoxystyryl substituted azetidinone prepared as described inExample 1 (0.552 g, 1.22 mmol) was hydrogenated (balloon pressure) indichloromethane (20 mL) over 0.052 g of 5% Pd on carbon for 3 hours atroom temperature. Filtration through celite and removal of solvent underreduced pressure afforded 0.555 g (100%) of the corresponding4β-[2-(3-methoxyphenyl)ethyl]azetidinone (compound 8) as a white solid.Recrystallization from hexanes-ethyl acetate gave long needles: mp134°-135° C.; [α]_(D) ²³ +38.6° (c=2.2, CHCl₃); IR (CHCl₃) 3010, 1755,1605, 1590, 1410 cm⁻¹ ; ¹ H NMR δ7.44-6.42 (m, 14, ArH), 4.97-4.84 (brt, 1, OCH₂ CH), 4.68 (t, 1, J=9 Hz, one of OCH₂), 4.64-4.59 (br d, 1, C₃H), 4.32 (s, 2, ArCH₂), 4.27 (dd, 1, J=6.4, 9.0 Hz, one of OCH₂), 3.77(s, 3, OCH₃), 3.57 (dt, 1, J=6.6, 4.9 Hz, C₄ H), 2.36 (br t, 1, J=8 Hz,ArCH₂ CH₂), 1.56-1.44 (br q, 1, ArCH₂ CH₂).

Anal. Calcd for C₂₀ H₂₄ N₄ O₆ : C, 73.66; H, 6.18. Found: C, 73.48; H,6.11.

Methyl5-[3β-(t-butyloxycarbonylamino)azetidin-2-one-4β-yl]-3-oxopentanoate

Lithium wire (0.548 g, 79 mmol) was added to 55 ml of ammonia at -78° C.and the mixture was warmed briefly to affect solution of the metal andthen recooled to -78° C. under positive argon pressure. The dark bluesolution was first treated with tert-butanol (12 mL). A solution of the1-benzyl-3β-(4-phenyloxazolidin-2-one-3-yl)-4β-[2-(3-methoxyphenyl)ethyl]azetidin-2-one(2.36 g, 5.17 mmol) in THF:tert-butanol (24 mL of a 3:1 mixture) wasthen added via cannula over a period of 5 minutes. After stirring forexactly 30 additional minutes, dry benzene (2 mL) was added. The bluecolor discharged after ca. 1 minute. Ammonium acetate (6.08 g, 79 mmol)was added, the cold bath removed, and the bulk of the ammonia wasdistilled off through a mercury bubbler. Solvent and any residualammonia were removed under reduced pressure at 40° C. The remainingwhite solid was suspended in 50 mL of THF:H₂ O (1:1), acidified to pH 8with 3N HCl, and treated with di-tert-butyl dicarbonate (1.8 mL, 7.8mmol). The two phase mixture was stirred rapidly for 12 hours and thenpartitioned between dichloromethane (200 mL) and H₂ O (50 mL). Theaqueous phase was reextracted with dichloromethane (50 mL) and thecombined organic phases were washed with 50 mL of saturated aqueousNaHCO₃, dried (Na₂ SO₄), and concentrated. Chromatography of the residueon 110 g of silica with 40% hexanes in ethyl acetate afforded 1.23 g ofthe partially purified dihydroaromatic3β-t-butyloxycarbonylamino-4β-[2-(5-methoxycyclohex-1,4-diene)ethyl]azetidine-2-oneas a waxy solid.

The diene product was dissolved in 25 mL of 50% methanol indichloromethane, treated with one drop of pyridine and ca. 1 mg of SudanIII dye (Aldrich Chemical Co.), and ozonolyzed at -78° C. until the redcolor discharged. Dimethyl sulfide (3 mL) was added, the cold bathremoved, and the reaction mixture stirred at room temperature for 5 hr.The light orange solution was poured into 100 mL of brine and extractedwith dichloromethane (1×200 mL, 1×50 mL). The combined organic layerswere dried (Na₂ SO₄) and concentrated. Chromatography of the residue on65 g of silica with 7% isopropanol in dichloromethane afforded methyl5-[3β-(t-butyloxycarbonylamino)azetidin-2-one-4β-yl]-3-oxopentanoate(0.97 g, 60% from 8) as an off-white solid. Recrystallization fromtoluene gave colorless needles: mp 122°-123° C.; [α]_(D) ²⁰ +48.6°(c=1.4, CHCl₃); IR (CHCl₃ ) 3430, 3420, 3340 (br), 3020, 2990, 1770,1720, 1510, 1370, 1250, 1160 cm⁻¹ ; ¹ H NMR (CDCl₃) δ6.51 (br s, 1, NHof β-lactam), 5.50 (br d, 1, BocNH), 5.05-4.98 (m, 1, C-3H), 3.83-3.71(m, 1, C-4H), 3.75 (s, 3, OCH₃), 3.48 (s, 2, COCH₂ CO), 2.74-2.56 (m, 2,CH₂ CH₂ CO), 1.93-1.74 (m, 2, CH₂ CH₂ CO), 1.45 (s, 9, tert-butyl).

Anal. Calcd. for C₁₄ H₂₂ N₂ O₆ : C, 53.49; H, 7.06. Found: C, 53.56; H,7.11.

The 3-t-BOC-aminoazetidinyl β-keto ester prepared as described above wasthen converted to the 3-hydroxy-1-carba(1-dethia)-3-cephem ester by theprocedures of the following Example 1.

EXAMPLE 1 Benzyl7β-(t-butyloxycarbonylamino)-3-trifluoromethylsulfonyloxy-1-carba(1-dethia)-3-cephem-4-carboxylateA. Diazo Transfer

To a 0° C. solution of the β-keto ester (1.13 g, 3.6 mmol) in 10 mL ofacetonitrile was added p-toluenesulfonyl azide (3.6 mL of a 1.5 Msolution in dichloromethane) and diisopropylethylamine (0.13 mL, 0.75mmol). The reaction was covered with foil, stirred at room temperaturefor 2 hours, and then partitioned between dichloromethane (100 mL) andbrine (50 mL) containing 10 mL of 0.5 M tartaric acid. The aqueous layerwas reextracted with dichloromethane (50 mL) and the combined organiclayers dried (Na₂ SO₄) and concentrated. Chromatography of the residueon 100 g of silica with 5% isopropanol in dichloromethane afforded 1.15g (94%) of the diazo keto ester as a white solid. Recrystallization fromethyl acetate-hexanes gave small needles: mp 136°-137° C. (dec); [α]_(D)²⁰ +65.8° (c=0.6, CHCl₃); IR (CHCl₃) 3440, 3420, 3360 (br), 3020, 2990,2150, 1770, 1720, 1650, 1510, 1440, 1370, 1320, 1160 cm⁻¹ ; ¹ H NMRδ6.49 (br s, 1, NH of β-lactam); 5.46 (d, 1, J=8.6, BocNH); 5.06 (dd, 1,J=4.8 Hz, 8.1 Hz; C₃ H); 3.85 (s, 3, OCH₃); 3.85-3.78 (m, 1, C₄ H);3.06-2.82 (m, 2, CH₂ CH₂ CO); 2.0-1.75 (m, 2, CH₂ CH₂ CO); 1.45 (s, 9,tert-butyl).

Anal. Calcd. for C₁₄ H₂₀ N₄ O₆ : C, 49.40; H, 5.92. Found: C, 49.47; H,5.93.

B. Transesterification

A solution of benzyl alcohol (20 mL, 193 mmol) and titanium isopropoxide(0.78 mL, 2.62 mmol) was stirred under vacuum (1 mm Hg) for 45 minutesto remove isopropanol. The flask was covered with foil, vented to argon,and the diazo β-keto methyl ester (0.953 g, 2.80 mmol) was added. Thesolution was heated at 36° C. for 42 hours, diluted with 60 mL ofdiethyl ether, and treated with saturated aqueous Na₂ SO₄ (3 mL). Themixture was stirred rapidly overnight, and then filtered through a padof celite. After removal of ether on a rotary evaporator, the benzylalcohol was distilled off using a kugelrohr oven (15 millitorr, 50° C.).Chromatography of the residue on 100 g of silica afforded thecorresponding diazo β-keto benzyl ester (0.837 g, 72%) as a white solid:mp 152°-153° (dec); [α]_(D) ²⁰ +55.6° (c=0.7, CHCl₃); IR (CHCl₃) 3450,3420, 3350 (br), 3020, 2990, 2150, 1770, 1715, 1655, 1510, 1370, 1305,1165 cm⁻¹ ; ¹ H NMR δ7.45-7.3 (m, 5, ArH), 6.4 (br s, 1, NH ofβ-lactam), 5.40 (d, 1, J=8.6, BocNH), 5.26 (s, 2, ArCH₂), 5.06 (br dd,1, J=4.5 Hz, 8.5 Hz C₃ H), 3.79 (dt, J=4.5, 8.5 Hz, C₄ H), 3.05-2.82 (m,2, CH₂ CH₂ CO); 2.0-1.73 (m, 2, CH₂ CH₂ CO), 1.45 (s, 9, tert-butyl).

Anal. Calcd. for C₂₀ H₂₄ N₄ O₆ : C, 57.68; H, 5.81. Found: C, 57.57; H,5.74.

C. Cyclization Rhodium (II)

A solution of the diazo β-keto benzyl ester (0.12 g, 0.29 mmol) in 6 mLof alumina filtered chloroform was heated to reflux and treated withrhodium (II) acetate dimer (1.5 mg, 0.0034 mmol). After heating for 20minutes, the mixture was placed in an ice bath, and treated sequentiallywith diisopropylethyl amine (0.10 mL, 0.6 mmol) andtrifluoromethanesulfonic anhydride (0.049 mL, 0.29 mmol). The reactionwas maintained at 0° C. for 15 minutes and then partitioned betweendichloromethane (75 mL) and 0.5 M aqueous tartaric acid (25 mL). Theorganic layer was dried (Na₂ SO₄) and concentrated to a light red oil,which was chromatographed on 20 g of silica with 6% ethyl acetate indichloromethane to afford benzyl7β-(t-butyloxycarbonylamino)-3-trifluoromethylsulfonyloxy-1-carba(1-dethia)-3-cephem-4-carboxylate(0.118 g, 78%) as a hard, colorless foam: [α]_(D) ²⁰ +31.5° (c=0.5,CHC₃); IR (CHCl₃) 3420, 3010, 2990, 1790, 1725, 1505, 1435, 1250, 1160,1140 cm⁻¹ ; ¹ H NMR (CDCl₃) δ7.46-7.3 (m, 5, ArH), 5.39 and 5.25 (two d(AB), 2, J=12.1 Hz, ArCH₂), 5.22-5.10 (m, 2, BocNH and C₇ H), 3.86 (dt,1, J ca. 4.2, 11.9 Hz, C₆ H), 2.63 (dd, 2, J=4.0, 8.8 Hz, C═CCH₂),2.20-2.08 and 1.78-1.60 (m, 2, CH--CH₂), 1.44 (s, 9, tert-butyl).

Anal. Calcd. for C₂₁ H₂₃ N₂ F₃ O₈ S: C, 48.46; H, 4.45. Found: C, 48.61;H, 4.49.

EXAMPLE 2 Benzyl7β-phenoxyacetylamino-3-trifluoromethylsulfonyloxy-1-carba(1-dethia)-3-cephem-4-carboxylate

To a solution of the 7β-t-butyloxyaminocarbacephalosporin (0.12 g, 0.23mmol) prepared as described in Example 6, in 1 mL of anisole was added 2mL of trifluoroacetic acid. After 30 minutes the solution wasconcentrated under reduced pressure (1 mm Hg) to an off-white solid.Phenoxyacetic anhydride (0.094 g, 0.33 mmol) and dichloromethane (2.5mL) were added to the solid, the mixture cooled to 0° C. and treatedwith diisopropylethyl amine (0.13 mL, 0.75 mmol). The solution wasstirred for 30 minutes and then partitioned between 0.5N aqueoustartaric acid (50 mL) and dichloromethane (75 mL). The organic phase waswashed with saturated aqueous NaHCO₃, dried (Na₂ SO₄), and concentratedto an oil. Chromatography on 20 g of silica gel with 6% ethyl acetate indichloromethane afforded 0.115 g (90%) of benzyl7β-phenoxyacetylamino-3-trifluoromethanesulfonyloxy-1-carba(1-dethia)-3-cephem-4-carboxylateas a hard foam: [α]_(D) ²³ +35.8° (c=0.6, CHCl₃); IR 3420, 3040, 1790,1740, 1695, 1605, 1525, 500, 1435, 1250 cm⁻¹ ; ¹ H NMR (CDCl₃)δ7.45-6.88 (m, 11, ArH and NH), 5.45-5.23 (m, 3, AB of ArCH₂ and C-7 H),4.54 (s, 2, ArOCH₂), 3.94 (ddd, J=3.5, 5.1, 1.7 Hz, C-6 H), 2.65-2.57(m, 2, CHCH₂ CH₂), 2.10-1.98 and 1.70-1.54 (m, 2, CHCH₂ CH₂).

EXAMPLE 37β-(2-thienylacetylamino)-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylicacid

p-Nitrobenzyl7β-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate isacylated in methylene chloride with 2-thienylacetyl chloride in thepresence of propylene oxide and then is deesterified to provide thetitle compound.

EXAMPLE 47β-(D-Phenylglycylamino)-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylicacid

7β-[D-2-(t-Butyloxycarbonylamino-2-phenyl)acetamido]-3-hydroxy-1-carba-3-cephem-4-carboxylicacid benzyl ester is reacted with triflic acid anhydride in the presenceof triethylamine to form the t-BOC protected3-trifluoromethylsulfonyloxy ester. The t-butyloxycarbonyl protectinggroup is removed with p-toluenesulfonic acid and the benzyl ester isremoved with aluminum chloride and anisole to provide the titlecompound.

EXAMPLE 5

p-Nitrobenzyl7β-Phenoxyacetylamino-3-chloro-1-carba(dethia)-3-cephem-4-carboxylate

A solution of 240 mg of p-nitrobenzyl7β-phenoxyacetylamino-3-trifluoromethylsulfonyloxy-1-carba(dethia)-3-cephem-4-carboxylateand 500 mg of lithium chloride in 3 ml of DMF was heated at 80° C. for5.5 h. The reaction mixture was then cooled, diluted with ethyl acetate,washed with water and with brine, dried over magnesium sulfate, andconcentrated by evaporation. The concentrate was chromatographed oversilica gel and the product eluted with methylene chloride-ethyl acetate.Evaporation of the eluate gave 112 mg of the title compound as a yellowfoam. The product was further purified by rechromatography over silicagel.

EXAMPLE 67β-Phenoxyacetylamino-3-chloro-1-carba(dethia)-3-cephem-4-carboxylicacid

Benzyl7β-phenoxyacetylamino-3-trifluoromethylsulfonyloxy-1-carba(dethia)-3-cephem-4-carboxylatewas heated at 80° C. in DMF with excess lithium chloride to yield thecorresponding 3-chloro-3-cephem benzyl ester. The benzyl ester group wasremoved with aluminum trichloride and anisole to provide the titlecompound.

EXAMPLE 77β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylicacid

syn-2-(2-Triphenylmethylthiazol-4-yl)-2-methoxyiminoacetyl chloride isreacted in acetonitrile with benzyl7β-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate inthe presence of triethylamine and the acylation product, benzyl7β-[2-(2-triphenylethylaminothiazol-4-yl)-2-methoxyiminoacetylamino]-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylateis treated with formic acid to remove the triphenylmethyl group and withaluminum chloride ih anisole to remove the benzyl ester group to providethe title compound.

We claim:
 1. The compound of the formula ##STR40## wherein R° ishydrogen or a conventional amino-protecting group and R₁ is acarboxy-protecting group.
 2. The compound of claim 1 wherein R° ishydrogen.
 3. The compound of claim 1 wherein R° is a protecting group ofthe formula ##STR41## wherein R°₁ is C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃-C₇ cycloalkyl, benzyl, nitrobenzyl, halobenzyl or methoxybenzyl.
 4. Thecompound of claim 2 wherein R°₁ is t-butyl, benzyl or nitrobenzyl. 5.The compound of claim 3 which is benzyl7β-t-butyloxycarbonylamino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate.